Which has a better advantage in terms of fewer cardiovascular events: Leqvio (inclisiran) or Repatha (evolocumab)?

Evolocumab Has Better Cardiovascular Outcomes Data Than Inclisiran

Evolocumab is the superior choice for reducing cardiovascular events because it has proven cardiovascular outcome trial data demonstrating a 15-20% reduction in major adverse cardiovascular events, while inclisiran lacks any completed cardiovascular outcomes trials. 1, 2

Direct Comparison of Cardiovascular Event Reduction

Evolocumab (Repatha) – Proven MACE Reduction

• The FOURIER trial demonstrated that evolocumab reduced the primary composite endpoint (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) by 15% (HR 0.85; 95% CI 0.79-0.92; P<0.001) over 2.2 years in 27,564 patients with established ASCVD. 1, 2
• The key secondary endpoint (cardiovascular death, MI, or stroke) was reduced by 20% (HR 0.80; 95% CI 0.73-0.88; P<0.001), representing an absolute risk reduction from 7.4% to 5.9%. 1, 2
• Evolocumab specifically reduced all strokes by 21% (HR 0.79; 95% CI 0.66-0.95; P=0.01) and ischemic stroke by 25% (HR 0.75; 95% CI 0.62-0.92; P=0.005). 1
• Extended follow-up data show evolocumab reduced cardiovascular mortality by 23% with continued benefit over time. 3

Inclisiran (Leqvio) – No Cardiovascular Outcomes Data

• The ORION-10 and ORION-11 trials evaluated inclisiran but measured only LDL-C reduction as the primary endpoint, not cardiovascular events. 1
• No cardiovascular outcome trials have been completed for inclisiran to demonstrate whether it reduces ASCVD event rates. 1
• The 2023 American Diabetes Association guidelines explicitly state that inclisiran trials did not assess cardiovascular outcomes. 1

LDL-C Reduction Comparison

Evolocumab

• Reduces LDL-C by approximately 59-61% from baseline, achieving median levels of 30 mg/dL. 1, 2, 4
• LDL-C reductions are observed early post-initiation and maintained long-term during up to 8.4 years of follow-up. 3

Inclisiran

• Reduces LDL-C by 43-55% depending on dosing (284mg vs 300mg). 4
• Administered on day 1, day 90, then every 6 months—less frequent than evolocumab's every 2-week or monthly dosing. 1

Guideline Recommendations

• The 2024 European Society of Cardiology guidelines recommend PCSK9 inhibitors (evolocumab, alirocumab) for patients not achieving LDL-C goals on maximum tolerated statin plus ezetimibe, based on proven cardiovascular outcomes data. 1
• The ESC guidelines note that PCSK9 monoclonal antibodies "resulted in significant reduction of non-fatal cardiovascular events" in outcomes trials. 1
• The 2023 American Diabetes Association guidelines acknowledge that evolocumab provides "substantial LDL-C reduction and cardiovascular benefit" in completed trials, while inclisiran data are limited to LDL-C endpoints. 1, 5

Clinical Algorithm for Selection

For patients with established ASCVD requiring additional LDL-C lowering beyond statin plus ezetimibe:

1. Choose evolocumab (140mg every 2 weeks or 420mg monthly) when the primary goal is proven cardiovascular event reduction. 1, 2

   • Particularly prioritize in very high-risk patients: recent ACS, multiple major ASCVD events, diabetes with target organ damage, or recurrent events within 2 years. 1, 6
   • Target LDL-C <55 mg/dL (or <40 mg/dL for recurrent events). 1

2. Consider inclisiran (284-300mg on day 1, day 90, then every 6 months) only when:

   • Adherence to frequent injections is a barrier. 1
   • The patient accepts that cardiovascular benefit is extrapolated from LDL-C reduction rather than proven in outcomes trials. 1

Critical Safety Considerations

• Both agents show no increase in adverse events including muscle symptoms, liver enzyme elevation, cognitive impairment, or hemorrhagic stroke at very low LDL-C levels (<25 mg/dL). 1, 6
• Evolocumab has 2.2-8.4 years of safety data from trials and real-world evidence in >51,000 patients. 3, 2
• Injection-site reactions occur slightly more frequently with evolocumab (2.1%) versus placebo (1.6%), but are generally mild. 2

Common Pitfall to Avoid

Do not assume equivalent cardiovascular benefit between evolocumab and inclisiran based solely on similar LDL-C lowering. The absence of completed cardiovascular outcomes trials for inclisiran means its impact on MI, stroke, and cardiovascular death remains unproven, whereas evolocumab has robust Level A evidence for MACE reduction. 1, 2